tbuckley/cabot-search huggingface dataset:
Evading the Toll booth: How “silent” flagellins may bind yet fail to activate TLR5
Authors: Hannah M. Baer, Shruti Sandilya, Theodore S. Steiner
Journal: Science Immunology (2023)

The nature of flagellin–Toll-like receptor 5 (TLR5) interactions, depending on binding to and activation of TLR5, may hold a key to the distinct differences in gut microbiome and intestinal immune function in different populations around the world (see related Research Article by Clasen et al .).
B cell– and T cell–intrinsic regulation of germinal centers by thymic stromal lymphopoietin signaling
Authors: Phillip P. Domeier, Ziaur S.M. Rahman, Steven F. Ziegler
Journal: Science Immunology (2023)

Long-lived and high-affinity antibodies are derived from germinal center (GC) activity, but the cytokines that regulate GC function are still being identified. Here, we show that thymic stromal lymphopoietin (TSLP) signaling regulates the GC and the magnitude of antigen-specific antibody responses. Both GC B cells and T follicular helper (T FH ) cells up-regulate the expression of surface TSLP receptor (TSLPR), but cell-specific loss of TSLPR results in distinct effects on GC formation and antibody production. TSLPR signaling on T cells supports the retention of antigen-specific B cells and T FH differentiation, whereas TSLPR in B cells regulates the generation of antigen-specific memory B cells. TSLPR in both cell types promotes interferon regulatory factor 4 (IRF4) expression, which is important for efficient GC activity. Overall, we identified a previously unappreciated cytokine regulator of GCs and identified how this signaling pathway differentially regulates B and T cell responses in the GC.
Association of metformin use and survival in patients with cutaneous melanoma and diabetes
Authors: Isabelle Krakowski, Henrike Häbel, Kari Nielsen, Christian Ingvar, Therese M L Andersson, Ada Girnita, Karin E Smedby, Hanna Eriksson
Journal: British Journal of Dermatology (2022)

Abstract Background Metformin use has been associated with improved survival in patients with different types of cancer, but research regarding the effect of metformin on cutaneous melanoma (CM) survival is sparse and inconclusive. Objectives To investigate the association between metformin use and survival among patients with CM and diabetes. Methods All adult patients with a primary invasive CM between 2007 and 2014 were identified in the Swedish Melanoma Registry and followed until death, or end of follow-up on 31 December 2017 in this population-based cohort study. Patients with both CM and type 2 diabetes mellitus were assessed further. Overall survival (OS) and melanoma-specific survival (MSS) were the primary endpoints. Cox proportional hazard models estimating crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were used comparing peridiagnostic use vs. nonuse of metformin. Dose response was evaluated based on defined daily doses. Results Among a total of 23 507 patients, 1162 patients with CM and type 2 diabetes mellitus were included in the final cohort, with a median follow-up time of 4.1 years (interquartile range 2.4–6.1). Peridiagnostic metformin use was associated with a significantly decreased risk of death by any cause (HR 0.68, 95% CI 0.57–0.81). Cumulative pre- and postdiagnostic metformin use was also associated with improved OS: the HR for prediagnostic use was 0.90 (95% CI 0.86–0.95) for every 6 months of use and the HR for postdiagnostic use ranged from 0.98 (95% CI 0.97–0.98) for 0–6 months to 0.59 (0.49–0.70) for 24–30 months of use. No association was found for metformin use and MSS. Conclusions Metformin use was associated with improved OS in patients with CM and diabetes regardless of timing (pre-, post- or peridiagnostic use) and followed a dose–response pattern. However, further research regarding the underlying mechanisms is warranted.
Anatomical contacts between sensory neurons and epidermal cells: an unrecognized anatomical network for neuro-immuno-cutaneous crosstalk
Authors: Matthieu Talagas
Journal: British Journal of Dermatology (2022)

Abstract Sensory neurons innervating the skin are conventionally thought to be the sole transducers of touch, temperature, pain and itch. However, recent studies have shown that keratinocytes – like Merkel cells – act as sensory transducers, whether for innocuous or noxious mechanical, thermal or chemical stimuli, and communicate with intraepidermal free nerve endings via chemical synaptic contacts. This paradigm shift leads to consideration of the whole epidermis as a sensory epithelium. Sensory neurons additionally function as an efferent system. Through the release of neuropeptides in intimate neuroepidermal contact areas, they contribute to epidermal homeostasis and to the pathogenesis of inflammatory skin diseases. To counteract the dogma regarding neurocutaneous interactions, seen exclusively from the perspective of soluble and spreading mediators, this review highlights the essential contribution of the unrecognized anatomical contacts between sensory neurons and epidermal cells (keratinocytes, melanocytes, Langerhans cells and Merkel cells), which take part in the reciprocal dialogue between the skin, nervous system and immune system.
Trends in keratinocyte skin cancer incidence, mortality and burden of disease in 33 countries between 1990 and 2017
Authors: Dorothy D Yang, Kim Borsky, Chinmay Jani, Conor Crowley, Jeremy N Rodrigues, Rubeta N Matin, Dominic C Marshall, Justin D Salciccioli, Joseph Shalhoub, Richard Goodall
Journal: British Journal of Dermatology (2022)

Abstract Background Keratinocyte cancers (KCs) are the most common type of cancer in the White population worldwide, with associated high healthcare costs. Understanding the epidemiological trends for KCs, namely basal cell carcinomas (BCCs) and cutaneous squamous cell carcinomas (SCCs), is required to assess burden of disease, project future trends and identify strategies for addressing this pressing global health issue. Objectives To report trends in BCC and SCC incidence, and SCC mortality and disability-adjusted life-years (DALYs). Methods An observational study of the Global Burden of Disease (GBD) database between 1990 and 2017 was performed. European Union countries and other selected high-income countries, including the UK and the USA, classified as having high-quality mortality data, were included. Annual age-standardized incidence rates (ASIRs), age-standardized death rates (ASDRs) and DALYs for each country were obtained from the GBD database. Trends were described using joinpoint regression analysis. Results Overall, 33 countries were included. For both BCC and SCC in 2015–2017, the highest ASIRs were observed in the USA and Australia. Males had higher ASIRs than females at the end of the observation period in all countries for SCC, and in all countries but two for BCC. In contrast, the highest ASDRs for SCC were observed in Australia and Latvia for males, and in Romania and Croatia for females. The highest DALYs for SCC for both sexes were seen in Australia and Romania. Over the observation period, there were more countries demonstrating decreasing trends in mortality than in incidence, and disparities were observed between which countries had comparatively high mortality rates and which had high incidence rates. Overall reductions in SCC DALYs were observed in 24 of 33 countries for males, and 25 countries for females. Conclusions Over the past 27 years, although trends in SCC incidence have risen in most countries, there is evidence that mortality rates have been decreasing. Burden of disease as assessed using DALYs has decreased in the majority of countries. Future work will explore potential explanatory factors for the observed disparity in trends in SCC incidence and mortality.
A skin disease survey of the Maasai in North Eastern Tanzania
Authors: Sidra S Khan, Darren M Ashcroft, Ncoza Dlova, Luly C Kini, Daudi Mavura, Rune N Philemon, Doriane Sabushmike, Rebekah Swan, Nirohshah Trialonis-Suthakharan, Tina Tian, Aakash Varma, Christopher E M Griffiths
Journal: British Journal of Dermatology (2022)
Secukinumab long-term efficacy and safety in psoriasis through to year 5 of treatment: results of a randomized extension of the phase III ERASURE and FIXTURE trials
Authors: Richard G Langley, Howard Sofen, Ignacio Dei-Cas, Kristian Reich, Bardur Sigurgeirsson, Richard B Warren, Carle Paul, Jacek C Szepietowski, Tsen-Fang Tsai, Isabelle Hampele, Ruquan You, Pascal Charef, Charis Papavassilis
Journal: British Journal of Dermatology (2022)

In the long-term extension study of the ERASURE and FIXTURE trials, the efficacy of secukinumab (a fully human anti-interleukin-17A monoclonal antibody) was demonstrated to have been maintained through to year 3 of treatment in moderate-to-severe plaque psoriasis.To assess the efficacy and safety of secukinumab through to year 5 of treatment in moderate-to-severe plaque psoriasis.Responders with ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) from two core trials - ERASURE and FIXTURE - were randomized 2 : 1 at year 1 (end of core trials) to either the same dose (300 or 150 mg, continuous treatment) or placebo (treatment withdrawal) every 4 weeks, until year 3 or relapse (> 50% reduction in maximal PASI from core study baseline). Partial responders (achieving PASI 50 but not PASI 75) at year 1 continued at the same dose as in the core trials. At year 3, all patients received open-label secukinumab treatment, with those on secukinumab 300 mg continuing on their dose, while those on secukinumab 150 mg or placebo received secukinumab 150 or 300 mg based on the physician's discretion. The study is registered on ClinicalTrials.gov with the identifier NCT01544595.Most patients randomized to placebo at year 1 relapsed, but the response was rapidly recaptured upon reinitiation of treatment. PASI responses were sustained with secukinumab through to year 5. The PASI responses for the 300 mg responders + partial responders group at year 1 (PASI 75/90/100: 86.8%/72.8%/45.9%) trended downwards until year 3 (PASI 75/90/100: 82.3%/58.4%/32.7%) and then remained stable through year 4 (PASI 75/90/100: 83.3%/60.1%/32.2%) until year 5 (PASI 75/90/100: 81.1%/62.8%/35.1%). Dermatology Life Quality Index showed sustained benefit up to year 5. Absolute PASI responses were maintained throughout the study. The most common adverse events (AEs) were infections and infestations, nasopharyngitis, and upper respiratory tract infections (URTIs). The overall exposure-adjusted incidence rate (EAIR; with 95% confidence interval) for all AEs was 139.9 (130.3-149.9). EAIRs for Crohn's disease and neutropenia were 0.1 (0.0-0.3) and 0.5 (0.3-0.8), respectively.The 4-year extension of two pivotal phase III trials demonstrated that secukinumab treatment was effective through to year 5 and improved quality of life in patients with moderate-to-severe plaque psoriasis. The most common AEs were infections and infestations, nasopharyngitis, and URTIs. The safety profile was consistent with that in the secukinumab phase II/III clinical development programme.
British Association of Dermatologists guidelines for the management of people with cutaneous squamous cell carcinoma <i>in situ</i> (Bowen disease) 2022
Authors: Ashish Sharma, Andrew J Birnie, Cristina Bordea, Seau Tak Cheung, Jasmine Mann, Colin A Morton, Asad Salim, Zeeshaan-Ul Hasan, Maria Hashme, Zahra Mansour Kiaee, M Firouz Mohd Mustapa, Lesley S Exton
Journal: British Journal of Dermatology (2022)

The overall objective of the guideline is to provide up-to-date, evidence-based recommendations for the management of squamous cell carcinoma in situ (SCC in situ). The document aims to: offer an appraisal of all relevant literature up to 13th August 2021, focusing on any key developments; address important, practical clinical questions relating to the primary guideline objective; provide guideline recommendations and if appropriate research recommendations.
The efficacy of learning programmes on hairstylists and barbers in the early detection of alopecia and scalp disorders in South Africa
Authors: Kiasha Govender, Wilbert Sibanda, Yolanda Lenzy, Ncoza Cordelia Dlova
Journal: British Journal of Dermatology (2022)

Journal Article The efficacy of learning programmes on hairstylists and barbers in the early detection of alopecia and scalp disorders in South Africa Get access Kiasha Govender, Kiasha Govender Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing Department of Dermatology, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa Correspondence: Kiasha Govender. Email: kiashagovender@gmail.com Search for other works by this author on: Oxford Academic Google Scholar Wilbert Sibanda, Wilbert Sibanda Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Software, Validation, Visualization, Writing - original draft, Writing - review & editing Biostatistics, Faculty of Health Sciences Management, Nelson Mandela University, Port Elizabeth, South Africa Search for other works by this author on: Oxford Academic Google Scholar Yolanda Lenzy, Yolanda Lenzy Conceptualization, Methodology, Validation, Writing - review & editing Lenzy Dermatology & Hair Loss Center, Chicopee, MA, USADepartment of Dermatology, University of Connecticut, MA, USA Search for other works by this author on: Oxford Academic Google Scholar Ncoza Cordelia Dlova Ncoza Cordelia Dlova Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Writing - original draft, Writing - review & editing Department of Dermatology, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 188, Issue 2, February 2023, Pages 308–309, https://doi.org/10.1093/bjd/ljac077 Published: 01 November 2022 Article history Received: 14 September 2021 Revision received: 23 October 2022 Accepted: 24 October 2022 Published: 01 November 2022 Corrected and typeset: 05 January 2023
Integrated safety analysis of baricitinib in adults with severe alopecia areata from two randomized clinical trials
Authors: Brett King, Arash Mostaghimi, Yutaka Shimomura, Abraham Zlotogorski, Gwang-Seong Choi, Ulrike Blume-Peytavi, Thierry Passeron, Katrin Holzwarth, Yves Dutronc, Jill McCollam, Fan Emily Yang, Sarah Stanley, Wen-Shuo Wu, Rodney Sinclair
Journal: British Journal of Dermatology (2022)

Baricitinib, an oral, selective, reversible Janus kinase (JAK)1/JAK2 inhibitor, is an approved treatment for adults with severe alopecia areata (AA) in the USA, European Union and Japan.To report safety data for baricitinib in patients with severe AA from two clinical trials including long-term extension periods.This analysis includes pooled patient-level safety data from two trials, an adaptive phase II/III trial (BRAVE-AA1) and a phase III trial (BRAVE-AA2) (ClinicalTrials.gov, NCT03570749 and NCT03899259). Data are reported in three datasets: (i) the placebo-controlled dataset (up to week 36): baricitinib 2 mg and 4 mg vs. placebo; (ii) the extended dataset (up to the data cutoff): patients remaining on continuous treatment with baricitinib 2 mg or 4 mg from baseline; and (iii) the all-baricitinib dataset (all-BARI, up to the data cutoff): all patients receiving any dose of baricitinib at any time during the trials. Safety outcomes include treatment-emergent adverse events (TEAEs), adverse events of special interest and abnormal laboratory changes. Proportions of patients with events and incidence rates (IR) were calculated.Data were collected for 1303 patients who were given baricitinib, reflecting 1868 patient-years of exposure (median 532 days). The most frequently reported TEAEs during the placebo-controlled period (based on the baricitinib 4-mg group) were upper respiratory tract infection, nasopharyngitis, headache, acne and elevated blood creatine phosphokinase (CPK). During the placebo-controlled period, the frequency of acne was higher with baricitinib than placebo, and elevated CPK was higher with baricitinib 4 mg than placebo and baricitinib 2 mg. In all-BARI, the IR of serious infections was low (n = 16, IR 0.8). There was one opportunistic infection (IR 0.1), and 34 cases of herpes zoster (IR 1.8). There was one positively adjudicated major adverse cardiovascular event (myocardial infarction) (IR 0.1), one pulmonary embolism (IR 0.1), three malignancies other than nonmelanoma skin cancer (IR 0.2) and one gastrointestinal perforation (IR 0.1). No deaths were reported.This integrated safety analysis in patients with severe AA is consistent with the overall safety profile of baricitinib. Some differences with atopic dermatitis were noted that may be attributable to the disease characteristics of AA.
Photoprotection for people with skin of colour: needs and strategies
Authors: Jean Krutmann, Jaime Piquero-Casals, Daniel Morgado-Carrasco, Corinne Granger, Carles Trullàs, Thierry Passeron, Henry W Lim
Journal: British Journal of Dermatology (2022)

Skin of colour or pigmented skin has unique characteristics: it has a higher eumelanin-to-pheomelanin ratio, more mature melanosomes, an increased amount of melanin distributed in the upper layers of the epidermis, and more efficient DNA repair compared with lighter skin. However, individuals with skin of colour are at a significant risk of skin damage caused by ultraviolet radiation, including the development of photodermatoses and photoageing changes such as uneven skin tone, and are predisposed to pigmentary disorders. In fact, one of the most common conditions leading to dermatology consultations by patients with skin of colour is photoexacerbated pigmentary disorders. Unfortunately, individuals with skin of colour may be less prone to engage in photoprotective measures, including the use of sunscreens. Physicians are also less likely to prescribe sunscreens for them. There is thus a clear need for better education on photodamage and for more efficient and suitable photoprotection in populations with skin of colour. However, this need has thus far only partially been met, and the development of sunscreen products designed to provide optimal photoprotection for people with skin of colour remains a challenge. Targeted sunscreens for individuals with skin of colour require optimal cosmetic appeal (leaving no white residue and not disrupting skin tone). They should include broad-spectrum [ultraviolet (UV)B/UVA] protection with high sun protection factor, as well as protection against long-wave UVA (UVA1) and visible light, as these wavelengths are capable of inducing or augmenting pigmentary disorders. They may also contain depigmenting agents for patients with pigmentary disorders.
Safety and efficacy of bimekizumab through 2 years in patients with moderate-to-severe plaque psoriasis: longer-term results from the BE SURE randomized controlled trial and the open-label extension from the BE BRIGHT trial
Authors: Diamant Thaçi, Ron Vender, Menno A de Rie, Curdin Conrad, David M Pariser, Bruce Strober, Veerle Vanvoorden, Maggie Wang, Cynthia Madden, Dirk de Cuyper, Alexa B Kimball
Journal: British Journal of Dermatology (2023)

BE SURE 1-year results demonstrated the superior efficacy of bimekizumab compared with adalimumab with no unexpected safety findings.To provide efficacy and safety data over 2 years of bimekizumab treatment compared with adalimumab from BE SURE and the BE BRIGHT open-label extension (OLE) in patients with moderate-to-severe plaque psoriasis.The 56-week double-blinded BE SURE phase III randomized controlled trial randomized patients 1 : 1 : 1 to bimekizumab 320 mg every 4 weeks (Q4W), bimekizumab 320 mg Q4W to week 16 then every 8 weeks (Q8W), or adalimumab 40 mg every 2 weeks to week 24 then bimekizumab 320 mg Q4W. After completing BE SURE, patients could enter the ongoing BE BRIGHT OLE, with possible dosing adjustments based on Psoriasis Area and Severity Index (PASI). The primary outcome in BE BRIGHT was incidence of treatment-emergent adverse events (TEAEs); safety data are reported by study period through week 104. Efficacy data are reported for the intention-to-treat population through week 104 by initial randomization group, with ≥ 90% improvement from baseline PASI (PASI 90) and 100% improvement (PASI 100) as key outcomes.Of the patients randomized to bimekizumab, 158 were assigned to Q4W, and 161 to Q4W/Q8W. At week 104, PASI 90 was achieved by 91.2% and 89.7%, and PASI 100 was achieved by 72.3% and 68.1%, for Q4W and Q4W/Q8W, respectively; comparable to week 16 results. Among the 159 patients randomized to adalimumab, responses rapidly and substantially increased after the week 24 bimekizumab switch; at week 104, 96.9% and 70.2% of patients achieved PASI 90 and PASI 100 respectively. Through weeks 24-104, the three most common TEAEs in any bimekizumab-treated group were nasopharyngitis, oral candidiasis and upper respiratory tract infection. Rates of serious TEAEs were low.Clinical responses observed through week 16 of BE SURE in patients randomized to bimekizumab were sustained through 104 weeks of treatment, regardless of Q4W or Q8W maintenance dosing. Response rates were also sustained through week 104 in patients who switched from adalimumab to bimekizumab at week 24, and were similar to those observed in the bimekizumab groups. Bimekizumab was well tolerated with no new safety signals.
<i>MaLAdapt</i> Reveals Novel Targets of Adaptive Introgression From Neanderthals and Denisovans in Worldwide Human Populations
Authors: Xinjun Zhang, Bernard Kim, Armaan Singh, Sriram Sankararaman, Arun Durvasula, Kirk E Lohmueller
Journal: Molecular Biology and Evolution (2023)

Adaptive introgression (AI) facilitates local adaptation in a wide range of species. Many state-of-the-art methods detect AI with ad-hoc approaches that identify summary statistic outliers or intersect scans for positive selection with scans for introgressed genomic regions. Although widely used, approaches intersecting outliers are vulnerable to a high false-negative rate as the power of different methods varies, especially for complex introgression events. Moreover, population genetic processes unrelated to AI, such as background selection or heterosis, may create similar genomic signals to AI, compromising the reliability of methods that rely on neutral null distributions. In recent years, machine learning (ML) methods have been increasingly applied to population genetic questions. Here, we present a ML-based method called MaLAdapt for identifying AI loci from genome-wide sequencing data. Using an Extra-Trees Classifier algorithm, our method combines information from a large number of biologically meaningful summary statistics to capture a powerful composite signature of AI across the genome. In contrast to existing methods, MaLAdapt is especially well-powered to detect AI with mild beneficial effects, including selection on standing archaic variation, and is robust to non-AI selective sweeps, heterosis from deleterious mutations, and demographic misspecification. Furthermore, MaLAdapt outperforms existing methods for detecting AI based on the analysis of simulated data and the validation of empirical signals through visual inspection of haplotype patterns. We apply MaLAdapt to the 1000 Genomes Project human genomic data and discover novel AI candidate regions in non-African populations, including genes that are enriched in functionally important biological pathways regulating metabolism and immune responses.